Project 3 SUMMARY Growing evidence suggests that EphA2 is an important therapeutic target in uterine cancer. Our recent integrative analysis of TCGA data further indicate that EphA2 upregulation is significantly correlated with poor survival. EphA2 is also expressed at high levels in the tumor vasculature and plays a critical role in regulating angiogenic functions. These findings, coupled with the low or absent expression of EphA2 in most normal adult tissues, make it a highly attractive therapeutic target. Despite its clinical benefit in patients with recurrent uterine cancer, dasatinib can result in substantial toxicity when combined with chemotherapy due to its ?off- target? engagement. Therefore, more specific therapeutic approaches for targeting EphA2 are needed. To achieve this goal, we have focused on systemically delivered short interfering RNA (siRNA) against EphA2 (EPHARNA) using a neutral nanoliposomal platform. Our overall hypotheses are that 1) EphA2 gene silencing using EPHARNA enhances the therapeutic response selectively in CAV1 overexpressing tumors; 2) Inhibition of MEK signaling increases the sensitivity to EphA2-targeted therapy in uterine cancer. The overall goal of this renewal proposal is to use EPHARNA for selective EphA2 targeting in uterine carcinoma and determine the underlying mechanisms of response and adaptive changes. The proposed Aims are complementary and will be pursued in close collaboration with the Cores.